6BVK
Ras:SOS:Ras in complex with a small molecule activator
Summary for 6BVK
| Entry DOI | 10.2210/pdb6bvk/pdb |
| Descriptor | GTPase HRas, Son of sevenless homolog 1, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (10 entities in total) |
| Functional Keywords | ras, sos, inhibitor, oncoprotein, protein-protein complex, mapk, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 95872.00 |
| Authors | Phan, J.,Abbott, J.,Fesik, S.W. (deposition date: 2017-12-13, release date: 2018-10-24, Last modification date: 2024-10-16) |
| Primary citation | Abbott, J.R.,Hodges, T.R.,Daniels, R.N.,Patel, P.A.,Kennedy, J.P.,Howes, J.E.,Akan, D.T.,Burns, M.C.,Sai, J.,Sobolik, T.,Beesetty, Y.,Lee, T.,Rossanese, O.W.,Phan, J.,Waterson, A.G.,Fesik, S.W. Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling. J. Med. Chem., 61:6002-6017, 2018 Cited by PubMed Abstract: Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2 protein levels at higher compound concentrations. PubMed: 29856609DOI: 10.1021/acs.jmedchem.8b00360 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.799 Å) |
Structure validation
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